Barrett's esophagus is the precursor of esophageal adenocarcinoma. Both Barrett's esophagus and esophageal adenocarcinoma are closely associated with gastroesophageal reflux. Screening endoscopy is therefore recommended for the evaluation of chronic gastroesophageal reflux symptoms. Endoscopic surveillance, performed in those identified with Barrett's esophagus, detects cancer at an early stage. However, the large majority of these cancers occur in previously undiagnosed Barrett's esophagus and nearly half of these persons have no history of gastroesophageal reflux symptoms. Identification of genetic risk factors would lead to more effective screening programs and improved understanding of the molecular pathogenesis of these diseases. Our prior case control study demonstrated familial aggregation of Barrett's esophagus and its associated cancers, which we termed Familial Barrett's Esophagus. We have since developed family recruitment and endoscopic screening methods to identify Familial Barrett's Esophagus. Recent molecular genetic studies have identified one putative locus and suggest the existence of at least one other locus linked to these diseases. These family recruitment, endoscopic screening, and genetic analysis methods will now be used to test the following central hypothesis: Familial Barrett Esophagus has a genetic basis. The specific aims of this proposal are: (1) To recruit and screen family members of esophageal adenocarcinoma patients, comparing age of cancer onset between probands classified as familial with those classified as apparently sporadic;(2) To perform endoscopic screening and measure the recurrence risk of Barrett's esophagus in siblings of probands with Barrett's esophagus and esophageal adenocarcinoma;and (3) To identify loci and map susceptibility genes associated with Familial Barrett's Esophagus. Using the multidisciplinary approach of our collaborative team of investigators, these aims will result in new information regarding a genetic predisposition to the development of Barrett's esophagus and esophageal adenocarcinoma.